Hysterectomy by Transabdominal Laparoscopy or NOTES (HALON)

Hysterectomy for Benign Gynaecological Disease by Natural Orifice Transluminal Endoscopic Surgery or Laparoscopy

Objective: To randomly compare hysterectomy by vaginal Natural Orifice Transluminal Endoscopic Surgery (vNOTES) versus laparoscopy uterus in women with benign gynecological pathology. Study design: Randomized controlled/single center/single-blinded/parallel-group/non-inferiority/efficacy trial. Study population: All women aged 18 to 70 years regardless of parity with a non-prolapsed uterus and a benign indication for hysterectomy. Primary study outcome parameters: successful removal of the uterus by the intended technique. Secondary outcomes: the proportion of women admitted to the in-hospital ward; postoperative pain scores; the total amount of analgesics used; postoperative infection; per- or postoperative complications; hospital readmission rates; duration of the surgical procedure; incidence and intensity of dyspareunia; sexual wellbeing; health-related quality of life; costs.

l1.Objectives of the HALON Trial The primary research questions of this IDEAL stage 2b efficacy trial are as follows: is a vNOTES (vaginal Natural Orifice Transluminal Endoscopic Surgery) hysterectomy at least as effective compared to the standard transabdominal laparoscopic approach (LSC) for removing a non-prolapsed uterus without the need for conversion to an alternative approach? (non inferiority design) Secondary research questions are: Do more women treated by vNOTES prefer to leave the day care unit on the day of surgery compared to LSC? Do women treated by vNOTES suffer from less pain compared to women treated by LSC in the first postoperative week? Is the removal of a uterus by vNOTES faster compared to LSC? Does a vNOTES cause more pelvic infection or other complications compared to LSC? Does a vNOTES result in more hospital readmissions within 6 weeks after surgery compared to LSC? Does a vNOTES approach result in more women reporting dyspareunia, less sexual wellbeing or less health-related quality of life at 3 or 6 months after surgery when compared to women treated by LSC? What are the direct and indirect costs up to 6 weeks after the surgical intervention of a vNOTES compared to LSC? 2. TRIAL DESIGN 2.1. Design A single center, single-blinded, parallel group randomized, non-inferiority efficacy trial. 2.2. Simple pilot randomized trial. 2.3. Time schedule Based upon the mean number of hysterectomies performed annually for benign gynecological disease at the department of Obstetrics and Gynecology of the participating center (168) the investigators estimate that the duration of recruitment will be 12 months. Based upon the follow up (6 months) and the period of analysis/reporting (3 months) the total study period will be 2 years. 2.4. Participating center Department of Obstetrics and Gynecology Imeldahospital Imeldalaan 9 2820 Bonheiden Belgium 3. ELIGIBILITY, CONSENT AND RANDOMIZATION 3.1. Screening and consent prior to surgery All women aged 18 to 70 years, regardless of parity, with a non-prolapsed uterus in need of a hysterectomy for benign indication are eligible for inclusion. 3.2. Determining eligibility All women aged 18 to 70 years, regardless of parity, with a non-prolapsed uterus in need of a hysterectomy for benign indication who provide consent to participation are eligible in the HALON trial and will be randomized before the procedure. 3.3. Randomization If the woman is eligible for the HALON trial, the trial secretary will obtain a randomized allocation the day before surgery. This will be done using a randomization list generated by a free computer software program offered by Research Randomizer (https://www.randomizer.org). The random sequence generation will be concealed using sequentially numbered opaque sealed envelopes. The envelope will be opened by the nurse assistant the day before surgery for practical logistic reasons. 3.4. Patients with strong preference for treatment A minority of women will express a clear preference for one of both treatments (e.g. strong desire to have no scar) and for this reason will not wish to be randomized between surgical treatments. To investigate how outcomes vary by choice, these women could be followed up in exactly the same way as for those women randomized into the HALON trial. A formal non-randomized follow-up of these women will not be done for logistical reasons. 3.5. Stratification of randomization A blocked randomization procedure will be used to avoid chance imbalances for the parameter 'uterine size'. 4. TREATMENT ALLOCATIONS 4.1. Surgical procedures The principal investigator, who has training and experience in both laparoscopy and NOTES, will perform all surgical procedures. He is therefore not blinded. All vNOTES participants will be blinded by three superficial non-therapeutic or "mock" skin incisions similar to those done with the laparoscopic technique. 4.1.1 vNOTES hysterectomy This is the surgical procedure done in the intervention arm of the HALON trial. 4.1.2 LSC hysterectomy This is the surgical procedure done in the control arm of the HALON trial. 5. FOLLOW-UP AND OUTCOME MEASURES 5.1. Clinical assessments 5.1.1 Format PROMs (Patient reported outcomes) will be collected using a postal questionnaire, which will include a combination of disease specific (Pain on sexual intercourse measured by VAS scale and SSFS Scale) and generic measurement instruments (EQ-5D). The postal questionnaires will be sent from the HALON Trial Office with postage paid envelopes two weeks before the due date. Reminders will be sent to patients if the questionnaire is not returned within one week of the due date and attempts will be made to contact the patient by phone if the questionnaire is not returned by two weeks after the due date. 5.1.2 Timing of assessments The primary outcome will be measured clinically at the end of the surgical procedure. In addition PROMs will take place at baseline (pain on sexual intercourse, health-related quality of life and sexual well being), the evening of the surgical intervention (in-hospital admission), during the first postoperative week (pain by VAS scores and analgetic drugs) and at 3 and 6 months (dyspareunia/ sexual well being/health related quality of life). Clinical physician assessment will take place the evening of the surgical intervention (in-hospital admission) and during the first six weeks following surgery (pelvic infection, surgical complications, hospital readmission rate). 5.2. Primary clinical outcome measure The proportion of women successfully treated by removing the uterus by the intended approach without conversion to another approach, using a dichotomous outcome measure, will be used as a measure of efficacy. 5.3. Secondary clinical outcome measures The following secondary outcomes will be measured: The proportion of women addmitted in-hospital for at least one night observation based on their own preference, as a dichotomous outcome. Postoperative pain scores, as an ordinal outcome, measured using a Visual Analogue Scale (VAS) twice daily from day 1 till 7 self-reported by the participating women. The VAS scores range from 0= no pain to 10= worst imaginable pain. Postoperative pain defined by the total amount of analgesics used as described in the standardized pain treatment protocol, as a continuous outcome. Postoperative infection as a dichotomous outcome. Per- or postoperative complications according to the Clavien- Dindo classification detected during the first six weeks of surgery, as a dichotomous outcome. The number of women readmitted to hospital within 6 weeks following surgery. Incidence and intensity of dyspareunia recorded by the participants at baseline, 3 and 6 months by self-reporting using a simple questionnaire and a Visual Analogue Scale (VAS) scale, as a dichotomous and ordinal outcome. The VAS scores range from 0= no pain to 10= worst imaginable pain. Sexual wellbeing at baseline, at 3 and 6 months by self-reporting the Short Sexual Functioning Scale (SSFS). The SSFS is a questionnaire with 7 multiple choice open ended questions. Health related quality of life, at baseline, at 3 and 6 months by self-reporting the EQ-5D-3L scale. The EQ-5D-3L scale is a questionnaire on 5 domains with 3 open ended questions and a scale from 0= worst possible health-related quality of life to 100= best possible health-related quality of life. Duration of surgery measured as the time in minutes from the insertion of the bladder catheter to the end of vaginal/abdominal wound closure, as a continuous outcome. 5.4.The direct and indirect costs up to 6 weeks after the hysterectomy of the vNOTES technique compared to LSC. 6. ACCRUAL AND ANALYSIS 6.1. Sample size The sample size for the primary outcome of this trial has been chosen to give good statistical power to preclude any clinically important inferiority of vNOTES compared to laparoscopy and is based on evidence retrieved from a Dutch prospective cohort study. Based on the power calculations for the primary outcome and assuming a loss-to-follow-up rate of 15% we decided to include 66 study participants in the HALON trial. 6.2. Projected accrual and attrition rates Based upon the mean number of hysterectomies performed annually at the department of Obstetrics and Gynecology of the participating center (168) the investigators anticipate that the duration of recruitment will be 12 months. Based upon the follow up (6 months) and the period of analysis/reporting (3 months) the total study period will be 2 years. First publication will be possible within four years of trial commencement. The sample size calculations have allowed for a 15% loss to follow up rate. In order to minimize rates of attrition a dedicated research secretary will be employed to optimize recruitment and follow up.

Successful removal of the uterus without conversion to another technique with or without morcellation

The number of women admitted in-hospital for at least one night observation based on their own preference after discharge from the day care unit, as a dichotomous outcome. The decision to discharge or to admit to hospital for the night will be based solely on the choice of the woman to return home the same day or stay overnight.

Postoperative pain scores, as an ordinal outcome, measured using a Visual Analogue Scale (VAS) twice daily (morning and evening) from day 1 till 7 selfreported by the participating women. VAS scores from 0 to 10 with 0 = no pain and 10= worst pain ever imaginable.

Postoperative pain defined by the total amount of analgesics used as described in the standardized pain treatment protocol, as a continuous outcome.

Postoperative infection defined by lower abdominal pain with fever > 38°C and positive clinical signs or laboratory findings, detected during the first six weeks of surgery, as a dichotomous outcome.

Intra- operative complications according to the Clavien- Dindo classification detected during the first six weeks of surgery, as a dichotomous outcome

The number of women readmitted to hospital within six weeks following surgery, as a dichotomous outcome.

Duration of surgery measured as the time in minutes from the insertion of the bladder catheter to the end of vaginal/ abdominal wound closure, as a continuous outcome

Incidence of vaginal dyspareunia recorded by the participants at 3 months by self-reporting using a simple questionnaire.

Incidence of vaginal dyspareunia recorded by the participants at 6 months by self-reporting using a simple questionnaire

Incidence of pelvic dyspareunia recorded by the participants at 3 months by self-reporting using a simple questionnaire.

Incidence of pelvic dyspareunia recorded by the participants at 6 months by self-reporting using a simple questionnaire.

Health-related quality of life at 3 months by self-reporting the EQ-5D scale.The reported values for the health-related quality of life are self-reported values using the VAS part of the two part EQ-5D-3L questionnaire. The scale ranges from 0 (worst quality) to 100 (best quality).

Health-related quality of life at 6 months by self-reporting the EQ-5D scale. The reported values for the health-related quality of life are self-reported values using the VAS part of the two part EQ-5D-3L questionnaire. The scale ranges from 0 (worst quality) to 100 (best quality).

Sexual wellbeing at baseline, at 3 and 6 months by self-reporting using the SSFS (Short Sexual Function Scale). The SSFS is a questionnaire of 7 open ended questions on sexual wellbeing.

Calculating the comparative direct costs in USD of both techniques up to 6 weeks after the surgical intervention

Inclusion Criteria: All women aged 18 to 70 years regardless of parity, with a non-prolapsed uterus in need of a hysterectomy for benign indication Written informed consent obtained prior to surgery Exclusion Criteria: History of rectal surgery Suspected rectovaginal endometriosis Suspected malignancy History of pelvic inflammatory disease, especially prior tubo-ovarian or pouch of Douglas abscess Active lower genital tract infection e.g. Chlamydia, N. gonorrhoeae Virgo Pregnancy Failure to provide written informed consent prior to surgery

Interim analyses of major endpoints will be supplied, in strict confidence, to an independent Data Monitoring and Ethics Committee (DMEC) along with updates on results of other related studies, and any other analyses that the DMEC may request.

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